1. Field of the Invention
The Present invention provides a method of treating ocular hypertension or glaucoma. Particularly, the invention provides a method, which can enhance the effect of known compounds synergistically and can reduce the occurrence of unfavorable side effects.
2. Related Art
Among prostaglandin compounds (hereinafter referred as "PG" or "PGs") having 20 carbon atoms in their basic structure and being called "eicosanoids", PGF.sub.2 .alpha. and PGF.sub.2 .alpha. a isopropyl ester have been known to have an ocular hypotensive activity (Bahram Resul and Johan Stjernschantz "Structure-Activity Relationships of Prostaglandin Analogues as Ocular Hypotensive Agents" Cardiovascular & Renal-Overview, 781-795 1993, Current Drugs Ltd.; Carl B. Camras et al., Survey of Ophthalmology Vol.41 [Suppl 2], S61-S68, 1997, the disclosures of all of these prior arts are herein expressly incorporated by reference). These compounds have been tried in the treatment of glaucoma and ocular hypertension. However, because of their side effects, including a transient increase in intraocular pressure preceding their ocular hypotensive effect, and strong hyperemia of conjunctiva and ocular stimulation, they have not been applied for clinical use so far. Generally, it has been believed that the biological and pharmacological effect of a PG is expressed via a receptor specific to the PGF. PGF.sub.2 .alpha. and PGF.sub.2 .alpha. isopropyl ester are known to have high affinity for the FP receptor, i.e. they act as FP receptor agonists (Bahram Resul et al., Survey of Ophthalmology Vol.41 [Suppl 2], S47-S52, 1997, the disclosures of this prior art is herein expressly incorporated by reference). In addition, a novel prostaglandin compound which acts as a FP-receptor agonist has also been reported (M. Hellberg et al. IOVS vol. 39 No. 4, 1961 Mar. 15, 1998, the disclosure of this prior art is expressly incorporated by reference).
Recently, Latanoprost (general name), a FP-receptor agonist type PG compound which has a high affinity for the FP receptor, has been developed during the study of the ocular hypotensive effect of PGF, a isopropylester. Latanoprost has a basic structure with a different number of carbon atoms from eicosanoids. The structure of Latanoprost is (+)-isopropyl-Z-7-{(1R,2R, 3R, 5S)-3, 5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl] cyclopentyl}-5-heptenoate. This compound has been reported to have an ocular hypotensive activity (Johan Stjerschantz et al., Drugs of the Future vol. 17, No. 8, 691-704, 1992; Johan Stjerschantz et al., Advances in Prostaglandin, Thromboxane, and Leukotriene Research, vol. 23 513-518, 1995; EP-A0364417 (corresponds to U.S. Pat. No. 5,296,504 and JP-A-03-501025), the disclosures of all of these prior arts are herein expressly incorporated by reference). However, the desired effect of Latanoprost has not been segregated from hyperemia of conjunctiva, an adverse side effect, and other side effects including iris pigmentation, uveitis and macula edema have also been reported (Goran Selen et al., Survey of Ophthalmology vol. 41, [Suppl 2], S125-S128, 1997; Perj Wistrand et al., Survey of Ophthalmology vol. 41, [Suppl 2], S129-S138, 1997; Jonathan A. Rowe et al. American Journal of Ophthalmology vol. 124, No. 5 683-685, 1997; Ronald E. Warwar et al., Ophthalmology vol. 105, No. 2, 263-268, 1998, the disclosures of all of these prior arts are herein expressly incorporated by reference). Further, it was reported recently that the FP receptor may play a significant role in iris pigmentation(Tadashi Nakajima et al., Abstract of The 6 th Meeting of Japanese Glaucoma Society, 136, 1995, the disclosure of this prior art is herein expressly incorporated by reference).
On the other hand, there are some non-FP receptor agonist type PG compounds, such as compounds having high affinity for the DP receptor or no substantial affinity for conventional PG receptors, known to have an ocular hypotensive activity (Carl B. Camras et al., Id). Compounds which do not have substantial affinity for conventional PG receptors include isopropyl unoprostone (general name) (Yasumasa Goh et al. Japanese Journal of Ophthalmology vol. 38, 236-245, 1994, the disclosure of this prior art is herein expressly incorporated by reference.) The structure of isopropyl unoprostone is (+) isopropyl-Z-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2(3-oxeodecyl)cyclopentyl] hept-5-enoate and is classified as a docosanoid having 22 carbon atoms in its basic structure. This compound is also known as one of PG metabolites since it has an oxo-group in place of hydroxy group on the carbon atom of position 15 (a so called "15-keto" type) and the carbon atoms of the positions 13 and 14 are linked through a carbon-carbon single bond(a so called "13,14-dihydro" type). The fact that this compound has an ocular hypotensive activity was described in EP-A-0308135 (corresponding to U.S. Pat. No. 5,001,153 and JP-A-02-108, the disclosures of these prior arts are herein expressly incorporated by reference).
The prior art does not describe nor suggest the combination of a FP receptor agonist type PG compound and a non-FP receptor agonist type PG compound, or any synergistic effects between these compounds. There is no teachings that the combination may reduce adverse side effects.